Background: Hemodialysis is the majority treatment modality for renal disease, and improvements in its delivery are desperately needed to curb the staggering 20% annual mortality rate for patients with endstage renal failure. Recent physiologic and observational studies have highlighted improved outcomes with more frequent hemodialysis. Clinical trials are now needed to establish the efficacy of this promising treatment. Objectives: The Renal Research Institute/University of Western Ontario Clinical Consortium seeks to conduct a randomized controlled trial of 200 patients comparing short daily 6 times per week hemodialysis (target standard Kt/V of 3.5 +/- 0.5 per week) against conventional 3 times per week hemodialysis (target equilibrated KtN of 1.2 +/- 0.1 per session, approximately equal to a standard Kt/V of 2.2 per week). Patients will be followed for 12 to 18 months. The aims of this study include: 1) to determine if the improvements in intermediate cardiovascular, social, nutritional, metabolic, and economic outcomes with daily over conventional hemodialysis, which our consortium has documented in observational studies, persist in a randomized controlled trial, 2) to quantify the adverse events and define potential risks associated with short-daily hemodialysis, and 3) to develop ancillary substudies advancing our knowledge of the physiology of daily hemodialysis. Key design elements to this trial include 1) stratification of the randomization by center and patient preference for in center or home hemodialysis, 2) a run in period of 2 weeks on in center daily hemodialysis, 3) careful standardization of specific co-interventions to provide optimal care and to avoid potential bias associated with the unblinded nature of the trial, and 4) statistical methods which account for missing data due to death and transplantation, and the multiple comparisons on intermediate outcomes used in the trial. Implications: This study will guide the feasibility, sample size and cost of a definitive clinical trial, which examines the effectiveness of daily hemodialysis to prevent death and hospitalization.